Natural killer (NK) cells are best known for their capacity to kill tumors. However, they also play an important role in innate defense against pathogens, especially herpes viruses, such as cytomegalovirus (CMV). The molecular basis for this apparent specificity has heretofore not been understood. In recent studies, however, the applicant's laboratory has discovered that the mouse NK cell orphan activation receptor, Ly49H, is involved in resistance to murine CMV (MCMV), and accounts for the previously described genetic locus for resistance to MCMV, termed Cmv1. In the genetic absence of Ly49H expression or when an anti-Ly49H-specific monoclonal antibody is injected into resistant mice, MCMV replication is not restrained and the infection is lethal, indicating that Ly49H is vital to NK cell mediated resistance to MCMV. These data strongly suggest the hypothesis that Ly49H is an activation receptor that recognizes MCMV infected cells. The current application proposes to examine this hypothesis in detail. In particular, the following specific aims are proposed to: 1) Study the genetics of Ly49H in MCMV resistance; 2) Determine the virus specificity of Ly49H; 3) Determine the basic characteristics of the Ly49H response and find evidence for specificity in vivo; 4) Detect the ligand for Ly49H on MCMV infected cells; and 5) Clone the Ly49H ligand from MCMV infected cells. Thus, these studies will provide significant new insight into pathogen control by NK cells.